Tak1, a novel prostate cancer tumor suppressor

描述(申请人提供)：转化生长因子β激活蛋白1(Tak1)是一种由MAP3K7基因编码的丝氨酸-茶氨酸蛋白激酶。Tak1是MAP激酶家族中的一员，最初被认为是非典型(非Smad)转化生长因子？但现在已知是许多细胞内信号转导通路的中心信号分子，包括白介素1、肿瘤坏死因子、Toll和Wnt/？-catenin通路。因此，它被认为是一种重要的调节分子，整合了参与生长和分化的多条途径。人们对Tak1在正常前列腺或前列腺癌中的作用知之甚少。我们最近证实，在大约38%的原发性前列腺癌中，Tak1基因缺失。在同一研究人群中，Tak1缺失的患病率相当于PTEN缺失的患病率。Tak1缺失与高Gleason评分显著相关。初步数据支持Tak1基因缺失在前列腺癌发生中的作用。基于这些初步数据和Tak1作为微环境多种信号的关键整合因子的已知作用，我们提出了Tak1是前列腺癌的肿瘤抑制因子的假设，并且Tak1的功能是调节前列腺癌上皮细胞的生长和/或分化以响应微环境。我们将用结合高通量遗传学、细胞生物学和动物模型研究的多学科方法来检验这一假设。提出了三个目标。目的1)Tak1缺失与Gleason分级的关系；2)体内前列腺特异性Tak1缺失；3)肿瘤微环境在Tak1缺乏症中的作用。如果我们的假设是正确的，这些研究是有意义的，因为它们将：1)确定Tak1缺失与前列腺癌进展预后标志物的关联；2)确定Tak1是前列腺癌抑制因子；3)确定Tak1在肿瘤微环境中的作用。确定Tak1在前列腺癌发生中的作用和潜在的基因-基因相互作用也很重要，因为它们可能导致前列腺癌治疗靶向的新策略。与公共健康相关：前列腺癌是一种致命的疾病，在美国每六名男性中就有一人患有前列腺癌。我们在染色体6q15上发现了一个潜在的前列腺癌抑制基因，即MAP3K7基因。我们的研究将测试该基因是否为前列腺癌肿瘤抑制基因，并询问其下游靶点。

DESCRIPTION (provided by applicant): TGF beta-activated kinase 1 (Tak1) is a serine-theonine kinase encoded by the MAP3K7 gene. Tak1, a member of the MAP kinase family, was originally identified as a downstream target of non-canonical (non-Smad) TGF-? signaling, but is now known to be a central signaling molecule for a number of intracellular signal transduction pathways, including the interleukin 1, TNF, Toll, and Wnt/?-catenin pathways. As such it is considered an important regulatory molecule that integrates multiple pathways involved in growth and differentiation. Little is known about the role of Tak1 in the normal prostate or in prostate cancer. We recently demonstrated deletion of the Tak1 locus in approximately 38% of primary prostate tumors. The prevalence of Tak1 deletion was equivalent to the prevalence of PTEN deletions in the same study population. There was significant association between loss of Tak1 and high Gleason score. Preliminary data support a role for loss of Tak1 in prostate tumorigenesis. Because of these preliminary data and the known role of Tak1 as a key integrator of multiple signals from the microenvironment, we propose the hypothesis that Tak 1 is a tumor suppresser for prostate cancer and that Tak1 functions to regulate growth and or differentiation of prostate epithelial cells in response to the microenvironment. We will test this hypothesis with a multidisciplinary approach that combines high throughput genetics with cell biology and animal model studies. Three aims are proposed. Aim 1) Association of Tak1 deletion with Gleason Grade; Aim 2) Prostate-Specific Deletion of Tak1 In Vivo; Aim 3) The role of the tumor microenvironment in Tak1 deficiency. If our hypothesis is correct these studies are significant because they will: 1) Determine the association of Tak1 deletion with prostate tumor progression prognostic markers 2) Identify Tak1 as a prostate tumor suppressor 3) Determine the role of Tak1 in the context of the tumor microenvironment. Identification of the role of Tak1 in prostate tumorigenesis and potential gene-gene interactions are also important because they may lead to novel strategies for prostate cancer therapeutic targeting. PUBLIC HEALTH RELEVANCE: Prostate cancer is a deadly disease that affects one in six men in the US. We have identified a potential prostate cancer tumor suppressor gene located on chromosome 6q15, the MAP3K7 gene. Our studies will test if this gene is a prostate cancer tumor suppressor and interrogate its downstream targets.